SHANK3
protein-codingSH3 and multiple ankyrin repeat domains 3, the group of Sterile alpha motif domain containing|Ankyrin repeat domain containing|PDZ domain containing
Gene summary
This gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation. Mutations in this gene are a cause of autism spectrum disorder (ASD), which is characterized by impairments in social interaction and communication, and restricted behavioral patterns and interests. Mutations in this gene also cause schizophrenia type 15, and are a major causative factor in the neurological symptoms of 22q13.3 deletion syndrome, which is also known as Phelan-McDermid syndrome. Additional isoforms have been described for this gene but they have not yet been experimentally verified. [provided by RefSeq, Mar 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~58.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011652
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0013498
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011652
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011652
Submitter: ClinGen
The relationship between *SHANK3* and autosomal dominant Phelan-McDermid syndrome was first suggested in 2001, when a balanced translocation disrupting the *SHANK3* gene was reported (Bonaglia et al., PMID: 11431708). The first *SHANK3* sequence variants were reported in 2007 (Durand et al., PMID: 17173049). *SHANK3* encodes a scaffolding protein in the postsynaptic density of glutamatergic synapses and plays a critical role in synaptic function. Phelan-McDermid syndrome can be caused by defects in *SHANK3* or by large deletions involving additional genes (also known as 22q13.3 deletion syndrome) that are responsible for the varied phenotype and severity amongst individuals. The syndrome is characterized by neonatal hypotonia, global developmental delay, intellectual disability, severely delayed or absent speech, autism spectrum disorder, seizures, neuroimaging abnormalities, and mild facial dysmorphism. Thirteen variants (frameshift, nonsense, and missense) that have been reported in 14 probands in three publications (PMIDs: 23758760, 25188300, 29719671) are included in this curation. Variants occurred *de novo* in all instances in which parental DNA was available. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is haploinsufficiency. This gene-disease relationship is also supported by *in vitro* functional assays, rescue experiments and animal models. In summary, there is definitive evidence supporting the relationship between *SHANK3* and autosomal dominant Phelan-McDermid syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 12, 2018 (SOP Version 6). As of October 2025, this record underwent administrative updates to include edits to the evidence summary and update scoring to be consistent with SOP Version 11. No new evidence was added, and the classification remains the same.
Inheritance Pattern: AD
Disease ID:MONDO:0011652
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011652
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011652
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Neurologic
Intervention: General
Rationale: There is evidence that variants in this gene are also involved in autism-related disorders; Deletions have been described as responsible for feaures of Chromosome 22q13.3 deletion syndrome; Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: There is evidence that variants in this gene are also involved in autism-related disorders; Deletions have been described as responsible for features of Chromosome 22q13.3 deletion syndrome
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SHANK3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript . Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 26 | 2 | 31 | ||
| missense | 5 | 68 | 11 | 1 | 85 | |
| nonsense | 2 | 1 | 1 | 4 | ||
| start loss | 0 | |||||
| frameshift | 5 | 1 | 1 | 7 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 2 | |||
| Total | 7 | 8 | 74 | 37 | 3 | 129 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001358973.1 | 24 | Standard | |
| Ensembl | ENSP00000489147.3 | 19 | Standard | |
| Ensembl | ENSP00000499632.1 | 2 | Standard | |
| Ensembl | ENSP00000499632.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| shank3a | Danio rerio | Structure: Rohon-Beard neuron Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glutamatergic synapse - Homo sapiens (human)
- Developmental Biology
- Neuronal System
- Signaling events regulated by Ret tyrosine kinase
- Neurexins and neuroligins
Biological Process
- MAPK cascade
- axon guidance
- synapse assembly
- learning
- memory
Molecular Function
- actin binding
- protein binding
- protein C-terminus binding
- zinc ion binding
- SH3 domain binding
Cellular Component
- cytosol
- ionotropic glutamate receptor complex
- postsynaptic density
- cell junction
- dendrite
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000262795
- Coding exons
- 23
- Length
- 58884
- Individuals with no LoFs
- 124105
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 124107
- p
- 0.00000806
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.74 | 571 | 884 | 0.646 | 0.0000599 | 10881 |
| Missense (PolyPhen) | 197 | 427.26 | 0.46108 | 4590 | ||
| Synonymous | -3.40 | 492 | 405 | 1.21 | 0.0000297 | 3824 |
| Loss of Function | 6.36 | 2 | 51.0 | 0.0392 | 0.00000262 | 666 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000089 | 0.0000089 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00017 | 0.00017 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance. Interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and HOMER, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction through the interaction with Arp2/3 and WAVE1 complex as well as the promotion of the F-actin clusters. By way of this control of actin dynamics, participates in the regulation of developing neurons growth cone motility and the NMDA receptor-signaling. Also modulates GRIA1 exocytosis and GRM5/MGLUR5 expression and signaling to control the AMPA and metabotropic glutamate receptor- mediated synaptic transmission and plasticity. May be required at an early stage of synapse formation and be inhibited by IGF1 to promote synapse maturation. {ECO:0000269|PubMed:24132240}.;
- Disease
- DISEASE: Note=A chromosomal aberration involving SHANK3 is found in patients with chromosome 22q13.3 deletion syndrome. Translocation t(12;22)(q24.1;q13.3) with APPL2/DIP13B. {ECO:0000269|PubMed:11431708}.; DISEASE: Note=Defects in SHANK3 are associated with neuropsychiatric disorders such as autism spectrum disorders (ASD), bipolar affective disorders and early dementia onset. ASD are characterized by impairments in reciprocal social interaction and communication as well as restricted and stereotyped patterns of interest and activities. ASD include forms with moderate to severe cognitive impairment and milder forms with higher cognitive ability (Asperger syndrome). Gene duplication is associated with hyperkinetic neuropsychiatric disorders (PubMed:24153177) such as hyperactivity, auditory overstimulation, epilepsy and bipolar affective disorders, among others. {ECO:0000269|PubMed:24153177}.; DISEASE: Phelan-McDermid syndrome (PHMDS) [MIM:606232]: A developmental disorder with variable features. Common features include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behavior, and minor dysmorphic features. {ECO:0000269|PubMed:22892527, ECO:0000269|PubMed:23758760, ECO:0000269|PubMed:24132240}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Schizophrenia 15 (SCZD15) [MIM:613950]: A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. {ECO:0000269|PubMed:20385823}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.111
Essentials
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.794
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |